Optimizing catecholaminergic polymorphic ventricular tachycardia therapy in calsequestrin-mutant mice

Abstract

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal arrhythmia provoked by physical or emotional stress and mediated by spontaneous Ca2+ release and delayed after-depolarizations. Beta-adrenergic blockers are the therapy of choice but fail to control arrhythmia in up to 50% of patients. OBJECTIVE To optimize antiarrhythmic therapy in recessively inherited CPVT caused by calsequestrin (CASQ2) mutations. METHODS Murine heart rhythm telemetry was obtained at rest, during treadmill exercise, and after injection of epinephrine. The protocol was repeated after injection of different antiarrhythmic drugs. Results were then validated in human patients. RESULTS Adult CASQ2 mutant mice had complex ventricular arrhythmia at rest and developed bidirectional and polymorphic ventricular tachycardia on exertion. Class I antiarrhythmic agents (procainamide, lidocaine, flecainide) were ineffective in controlling arrhythmia. Propranolol and sotalol attenuated arrhythmia at rest but failed to prevent VT during sympathetic stimulation. The calcium channel blocker verapamil showed a dose-dependent protection against CPVT. Verapamil was more effective than the dihydropyridine L-type Ca2+ channel blocker nifedipine, and its activity was markedly enhanced when combined with propranolol. Human patients homozygous for CASQ2D307H mutation, remaining symptomatic despite chronic β-blocker therapy, underwent exercise testing according to the Bruce protocol with continuous electrocardiogram recording. Verapamil was combined with propranolol at maximum tolerated doses. Adding verapamil attenuated ventricular arrhythmia and prolonged exercise duration in five of 11 patients. CONCLUSION Verapamil is highly effective against catecholamine-induced arrhythmia in mice with CASQ2 mutations and may potentiate the antiarrhythmic activity of β-blockers in humans with CPVT2.

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation

“…With regard to targeted sites for effective pharmacotherapy, recent experimental data and preliminary clinical observations are of interest (18,26,28). In CASQ2 mutant mice, verapamil (a Ca 2ϩ -channel blocker) exhibited a dose-dependent protection against sympathetic stimulation-induced ventricular arrhythmia and its action was markedly enhanced when combined with propranolol (a ␤-blocker) (18), and clinically, combination therapy by adding verapamil to a ␤-blocker seemed more effective than ␤-blocker therapy alone in preventing exercise-induced arrhythmias in a limited number of patients with CPVT (18,28).…”

“…In CASQ2 mutant mice, verapamil (a Ca 2ϩ -channel blocker) exhibited a dose-dependent protection against sympathetic stimulation-induced ventricular arrhythmia and its action was markedly enhanced when combined with propranolol (a ␤-blocker) (18), and clinically, combination therapy by adding verapamil to a ␤-blocker seemed more effective than ␤-blocker therapy alone in preventing exercise-induced arrhythmias in a limited number of patients with CPVT (18,28). However, in a rat chronic heart failure model, SR Ca 2ϩ ATPase2a (SERCA2a) gene therapy restored SR Ca 2ϩ load and reduced RyR2 phosphorylation, thereby increasing the threshold of SOICR (without affecting the open probability of RyR2) and in turn decreased the SR Ca 2ϩ leak; consequently, SERCA2a gene therapy attenuated TA in vitro and catecholamine-sensitive ventricular arrhythmias in vivo in failing hearts (26).…”

“…Our study has demonstrated the ease with which BAS facilitates induction of DADs and/or DAD-mediated TA. Although most patients are benefited by taking ␤-blockers, many of them continue to experience arrhythmic spells and are impervious to therapy with other antiarrhythmic drugs (18,19,21,23,28). Similar to patients with Timothy syndrome (LQT8) (34), ICD therapy may cause repeated delivery of electrical shocks (electrical storm) due to first shock-induced activation of sympathetic tone.…”

“…By age of 40, cardiac events occur in 80% of patients and the mortality rate could be as high as 30 -50% (23). Clinical observations have shown that ␤-adrenergic blocking agents provide only incomplete protection and other antiarrhythmic agents such as quinidine, verapamil, and amiodarone are either ineffective or only partially efficacious (18,19,21,23,28). Of note, some patients need to resort to implantation of implantable cardioverter/defibrillators (ICD) and/or left cardiac sympathetic denervation and even to cardiac transplantation (23,39).…”

Catecholaminergic Polymorphic Ventricular Tachycardia in 2012

“…In one o n l y study, verapamil was the most effective antiarrhythmic drug in reducing ventricular arrhythmia in CASQ2 mutation carrying mice and humans. 45 Recently, it was discovered that flecainide prevented ventricular arrhythmias in a CASQ2 knock-out mouse model, presumably by directly targeting the underlying defect in CPVT. 46 Subsequently, we evaluated the efficacy and safety of this flecainide on top of conventional drug therapy in 33 mutation-carrying CPVT patients with continuous symptoms or ventricular arrhythmias.…”